Heterocyclic arylsulphones suitable for treating disorders that respond to modulation of the serotonin 5HT6 receptor
a technology of arylsulphones and arylsulphones, applied in the field of heterocyclic compounds, can solve the problems of their affinity and selectivity towards the 5htsub>6/sub>receptor or their pharmacological profile is not yet satisfactory
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I. Preparation of the Intermediates
a. Preparation of Sulfonyl Chlorides
a.1 3-Bromo-4-trifluoromethoxy-benzenesulfonyl chloride
[0278]2.0 g of 1-bromo-2-(trifluoro-methoxy)benzene (8.3 mmol) were dissolved in 30 ml of dichloromethane. At 0-5° C., 1.06 g of chlorosulfonic acid (9.13 mmol), dissolved in 3 ml of dichloromethane, were added dropwise. The reaction mixture was stirred for 30 min at room temperature. Additional 5.5 equivalents of chlorosulfonic in dichloromethane were added to drive the reaction to completion. Standard work-up was followed and silica gel chromatography with n-heptane-dichloromethane (6:4) as eluent gave 2.19 g of the title compound.
[0279]1H-NMR (CDCl3, 400 MHz): δ [ppm] 8.3 (d, 1H), 8.05 (dd, 1H), 7.5 (dd, 1H).
b. Preparation of 3-(3-aminophenyl)-pyrrolidines
b.1 1-(Methoxycarbonyl)-3-(3-aminophenyl)-pyrrolidine
b.1.1 1-(Methoxycarbonyl)-pyrroline
[0280]In a 5 l flask fitted with a mechanical stirrer and a thermocouple, were charged 500 g of powdered potassium c...
example 1
3-Trifluoromethoxy-N-[4-((S)-1-propyl-pyrrolidin-3-yl)-phenyl]-benzenesulfonamide and its hydrochloride
1.1 (S)-2-Phenyl-succinic acid dimethyl ester
[0290]5 g of (S)-2-phenyl succinic acid (25.75 mmol) were dissolved in 50 ml of methanol. At 4° C., 4.7 ml of thionyl chloride (64.37 mmol) were added dropwise. The reaction mixture was stirred at room temperature for 2 h, the solvents were evaporated under reduced pressure. The residue that remained was dissolved in diethyl ether, washed once with saturated aqueous NaHCO3 solution, reextracted with diethyl ether, and the combined organic layers dried over magnesium sulfate, filtered, and evaporated to dryness to yield 5.8 g of the desired product.
[0291]ESI-MS: 223.1 [M+H]+
1.2 (S)-2-Phenyl-butane-1,4-diol
[0292]2.54 g of lithium aluminium hydride (66.95 mmol) were suspended under ice cooling in 25 ml of tetrahydrofuran. 5.8 g of (S)-2-phenyl succinic acid dimethyl ester (25.75 mmol) dissolved in 25 ml of tetrahydrofuran were added slowly ...
example 2
4-Bromo-3-fluoro-N-[4-((S)-1-propyl-pyrrolidin-3-yl)-phenyl]-benzenesulfonamide
[0306]0.289 g of the desired product were obtained following the same synthetic procedure as described for 3-trifluoromethoxy-N-[4-((S)-1-propyl-pyrrolidin-3-yl)-phenyl]-benzenesulfonamide using commercially available 4-bromo-3-fluoro-benzenesulfonylchloride.
[0307]ESI-MS: 441.0 / 443.0 [M+H]+
[0308]1H-NMR (CDCl3): δ [ppm] 7.65 (m, 1H), 7.5 (m, 1H), 7.4 (m, 1H), 7.15 (d, 2H), 7.0 (d, 2H), 3.3 (m, 1H), 3.0 (m, 1H), 2.8 (m, 1H), 2.65 (m, 1H), 2.35-2.5 (m, 3H), 2.3 (m, 1H), 1.8 (m, 1H), 1.5 (m, 2H), 0.9 (m, 3H).
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